As reported in our aforesaid U.S. patent applications, we have discovered that certain 3-substituted-1-(.beta.-D-ribofuranosyl)-1,2,4-triazoles, notably the 3-carboxamide, 3-thiocarboxamide and 3-carboxamidines, possess potent antiviral activity. Those applications detail the preparation of precursors of the bioactive 1,2,4-triazole nucleosides (and corresponding cyclic and non-cyclic phosphorylated analogs) by processes involving either reaction of trimethyl-silylated 1,2,4-triazoles with O-acyl halo sugars, or acid-catalyzed fusion of appropriately 3-substituted 1,2,4-triazole with tetra-O-acyl sugar. Aminolysis of resulting 1-(.beta.-D-ribofuranosyl)-1,2,4-triazole-3-alkyl carboxylates affords the bioactive 3-carboxamide, while similarly formed 3-cyano-1-(.beta.-D-ribofuranosyl)-1,2,4-triazoles may be converted in straight forward fashion to corresponding 3-thiocarboxamides and 3-carboxamidines, respectively by reaction with hydrogen sulfide or ammonia.
In the later of our aforesaid applications, and in our application Ser. No. 340,332 filed Mar. 12, 1973 now U.S. Pat. No. 3,927,216, we report discovery of the antiviral activity of the known compounds 1,2,4-triazole-3-carboximide, and 1,2,4-triazole-3-thiocarboxamide, and preparation of the corresponding 1-.beta.-D-riboside by reaction of the former with the enzyme Nucleoside phosphorylase. These bioactive bases are but poorly soluble. We conceived that solubility and lipophilicity of the bioactive bases could be enhanced, and in the course of doing so have prepared a novel class of N-substituted 1,2,4-triazole analogs of the antiviral ribosides which, unlike the latter, are readily susceptible to hydrolytic cleavage under conditions encountered in vivo, generating the 3-substituted 1,2,4-triazole base in situ. Although we do not wish to be bound by any theory, we believe that base is then promoted enzymatically to corresponding 1(.beta.-D-ribofuranosyl)-1,2,4-triazole nucleosides and/or nucleotides enroute to formation of truly active metabolite. According to this invention, there are provided novel compounds of structure ##SPC1##
Wherein R.sub.1 is selected from the group consisting carboxamido, thiocarboxamido and carboxamidine groups and physiologically acceptably acid addition salts of the latter (in the case of bioactive compounds) or of cyano or alkylcarboxylate groups (in the case of intermediates useful in the synthesis of the former compounds). G in the foregoing structures is a hydrocarbon moiety (preferably linked through carbon to the triazole ring) chosen in one embodiment such that the bond G-N is activated toward hydrolysis to an extent sufficient to effect at least about 50% conversion to 3-R.sub.1 -1,2,4-triazole in about one hour at 37.degree. C in "simulated gastric fluid" (as used herein, a pH 1.3 solution consisting of 2.0 gm. NaCl, 7.0 ml. concentrated HCl and sufficient water to make up 1000 ml. solu.), as determined by ultraviolet spectroscopy. As candidates for the group G may especially be mentioned groups in which an electronegative atom such as nitrogen or oxygen is alpha to that carbon linked directly to nitrogen of the triazole ring. As to the former, see the N-carbamoyl-1,2,4-triazoles of H. Becker and V. Eisenschmidt, Journal f. prakt. Chemie 315, 640 (1973) and W. German Offen. 2,147,794. As to the latter, see, e.g., the 1,2,4-triazole N-carbonic acid esters of "The Chemistry of 1,2,4-triazoles" by K. T. Potts, Chem. Review 61, 87, (1961). The aforesaid publications are incorporated herein by reference. Preferred in the practice of the invention are compounds in which G is a nonglycosidic 1-(.alpha.-alkoxyalkyl) moiety i.e., a moiety of structure ##STR1## wherein R' and R" are, e.g., aliphatic groups having 1 to about 9 carbon atoms or aliphatic groups joined to form a cyclic ether having 4 (tetrahydrofuran-2-yl) or 5(tetrahydropyran-2-yl) ring carbons. Since all the evidence in our hands supports the proposition that G is cleaved in vivo, it is unlikely that bioactivity can be made to depend upon nice choice of R' and R", viz., they may bear physiologically acceptable substituents calculated not to interfere with hydrolytic scission of G following administration.